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Myelination in the brain may be key to ‘learning’ opioid addiction
Our brains, even in adulthood, continually adapt to what we do, strengthening or weakening neural pathways as we practice new skills or abandon old habits. Now, research by Stanford Medicine scientists has found that a particular type of neuroplasticity, known as adaptive myelination, can also contribute to drug addiction.
But the same adaptive myelination that is essential to learning, attention and memory has a dark side. In the new study in mice, researchers found that a single dose of morphine was enough to trigger the steps leading to myelination of dopamine-producing neurons — part of the brain’s reward circuitry — spurring the mice to seek out more of the drug. When myelination was blocked, the mice made no effort to find more morphine.
The new findings, to be published June 5 in Nature, show how using addictive drugs can drive maladaptive myelination of the brain’s reward circuitry, which in turn reinforces drug-seeking behavior.
Myelin matters
“Myelin development does not complete until we’re in our late 20s or early 30s, which is kind of fascinating,” said Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology and senior author of the study.
Even after such a protracted developmental period, special cells in the brain called oligodendrocytes continue to generate new myelin in some brain regions.
“What we’ve come to understand over the last decade or so is that myelin, in some parts of the nervous system, is actually plastic and adaptable to experience,” Monje said. “The activity of a neuron can regulate the extent to which its axon is myelinated.”
Research in neuroplasticity has mostly focused on changes that occur at synapses — where neurons meet and communicate with each other. Adaptive myelination adds a new layer to how our brains learn from experience.
Much of the foundational knowledge about adaptive myelination has come from Monje’s lab. In 2014, her team reported that stimulating the premotor cortex of mice increased the myelination of neurons there and improved limb movement. Subsequent studies by her lab and collaborators have found that mice need adaptive myelination for spatial learning — to navigate a maze, for example, or to remember a threatening situation.
Reward learning
In the new study, Monje’s team wondered whether adaptive myelination was involved in reward learning. The researchers generated a rewarding experience in mice by giving them cocaine or morphine, or by directly stimulating their dopamine-producing neurons using optogenetic techniques.
Within three hours of a single injection of cocaine or morphine or 30 minutes of stimulation, the researchers were surprised to see a proliferation of the specialized stem cells that are destined to become myelin-producing oligodendrocytes. The proliferation was isolated to a brain region known as the ventral tegmental area, which is involved in reward learning and addiction.
“We didn’t think one dose of morphine or cocaine would do anything,” said Belgin Yalcin, PhD, lead author of the new study and an instructor in neurology and neurological sciences. “But within three hours there was a change. A very mild change, but still a change.”
Both the speed and specificity of the changes were unexpected, the researchers said.
When researchers repeated the drug injections or brain stimulation for several days, then examined the mice a month later, they indeed found more oligodendrocytes and more myelinated dopamine-producing cells, with thicker myelin around their axons, again only in the ventral tegmental area.
Even a slight thickening of myelin — in this case, by several hundred nanometers — can affect brain function and behavior.
“Details matter in terms of myelin plasticity,” Yalcin said. “So little can make such a big difference in conduction velocity and the synchronicity of the circuit.”
Potent rewards
To see how the myelination translated into behavior, the researchers placed each mouse in a box where it could move freely between two chambers. In one chamber, the mice received a daily injection of morphine. (The researchers decided to focus on morphine because of its relevance to the opioid epidemic.) After five days, the mice strongly preferred the chamber where they had received the drug and would linger there, hoping for another hit.
The morphine stimulated the mice’s reward circuitry (specifically, the dopamine-producing neurons in the ventral tegmental area), increased the myelination of these neurons and tuned their brains for further reward-seeking behavior.
Curiously, when the researchers tested a food reward instead of morphine, the mice did not develop more food-seeking behavior, perhaps because the reward was less potent, the researchers said.
“You might not want your reward circuits to be modified by everyday kinds of rewards,” Monje said.
From mice to men
“In the healthy nervous system, adaptive myelination tunes circuit dynamics in a way that supports healthy cognitive functions like learning, memory and attention,” Monje said.
But as the new study demonstrates, the process can go awry, enhancing circuits that drive unhealthy behaviors or failing to enhance circuits required for healthy brain function.
In 2022, Monje’s lab reported that adaptive myelination could explain why some epileptic seizures worsen over time. The experience of seizures drives more myelination of the circuits involved, allowing faster and more synchronized signaling, which become more frequent and severe seizures. Her team also has found that reduced myelin plasticity contributes to “chemo-fog,” the cognitive impairments that often follow cancer treatment.
In the new study, the precise biochemical steps by which a drug reward leads to myelination are not completely clear. The researchers tried bathing oligodendrocyte precursor cells in dishes of morphine or dopamine and determined that neither chemical directly causes proliferation of these cells.
“A future direction would be to understand what exactly these myelin-forming cells are responding to that comes from the activity of dopaminergic neurons,” Yalcin said.
They found that a pathway known as BDNF-TrkB signaling is part of the story. When they blocked this pathway, the mice did not generate new oligodendrocytes and did not acquire a preference for the chamber where they received the drug.
“The mice just couldn’t learn where they received their morphine reward,” Monje said.
Ultimately, a better understanding of adaptive myelination might reveal new strategies to help people recover from opioid addiction. Perhaps the process can be reversed and an addiction unlearned.
“We don’t know whether these changes are permanent, but there’s reason to believe that they would not be,” Monje said. “We think that myelin plasticity is bidirectional — you can both increase myelination of a circuit and decrease myelination of a circuit.”
The study was supported by funding from the Gatsby Charitable Foundation, the Wu Tsai Neurosciences Institute NeuroChoice Initiative, the National Institute of Neurological Disorders and Stroke (grant R01NS092597), the NIH Director’s Pioneer Award (DP1NS111132), the National Institute for Drug Abuse (P50DA042012, T32DA035165 and K99DA056573), the National Cancer Institute (P50CA165962, R01CA258384 and U19CA264504), the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Cancer Grand Challenges and Cancer Research UK, a Maternal and Child Health Research Institute at Stanford University Postdoctoral Award, and a Dean’s Postdoctoral Fellowship at Stanford University.
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Early dark energy could resolve cosmology’s two biggest puzzles
A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.
Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.
Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.
The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.
“You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”
The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.
Big city lights
Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.
But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.
“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”
For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.
Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.
Galaxy skeleton
The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.
“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”
The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.
Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.
The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.
“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”
“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”
“We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”
This research was supported, in part, by NASA and the National Science Foundation.
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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions
A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.
The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.
“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.
“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.
The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.
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Folded or cut, this lithium-sulfur battery keeps going
Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.
The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.
After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.
The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.
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